Contribution of the TCR beta repertoire to Marek's disease genetic resistance in chicken

Authors: Hearn, Cari; Cheng, Hans

Submitted to: Viruses
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 2/11/2023
Publication Date: 2/22/2023
Citation: Hearn, C.J., Cheng, H.H. 2023. Contribution of the TCR beta repertoire to Marek's disease genetic resistance in chicken. Viruses. 15(3):607. https://doi.org/10.3390/v15030607.
DOI: https://doi.org/10.3390/v15030607

Interpretive Summary: Marek's disease (MD) is an important viral disease of chickens which causes tumors, leading to industry losses and expenditures to control disease. Use of genetically disease-resistant poultry stock is an important strategy to control disease and reduce costs to producers; understanding the underlying mechanisms of genetic resistance can improve rational breeding strategies. We examined the T cell immune systems of model MD-resistant and MD-susceptible chicken lines which share major histocompatability complex (MHC) genetics, in order to identify non-MHC differences which contribute to disease resistance., and found large differences in their T cell receptor repertoires at the genomic level and in response to infection. Improving our understanding of the T cell immune responses in genetically resistant birds is an important step towards producing birds with optimized immune responses to viral infections and vaccinations.

Technical Abstract: Marek’s disease (MD) is a lymphoproliferative disease of chickens induced by Marek’s disease virus (MDV), an oncogenic a-herpesvirus. MDV has increased in virulence, prompting continued efforts in both improved vaccines and enhanced genetic resistance. Model pairs of genetically MD-resistant and MD-susceptible chickens that were either MHC-matched or MHC-congenic allowed characterization of T cell receptor (TCR) repertoires associated with MDV infection. MD-resistant chickens showed higher usage of Vß-1 TCRs than susceptible chickens in both the CD8 and CD4 subsets in the MHC-matched model, and in the CD8 subset only in the MHC-congenic model, with a shift towards Vß-1+ CD8 cells during MDV infection. Long and short read sequencing identified divergent TCRß loci between MHC-matched MD-resistant and MD-susceptible chickens, with MD-resistant chickens having more TCR Vß1 genes. TCR Vß1 CDR1 haplotype usage in MD-resistant x MD-susceptible F1 birds by RNAseq indicated that the most commonly used CDR1 variant was unique to the MD-susceptible line, suggesting that selection for MD resistance in the MHC-matched model optimized the TCR repertoire away from dominant recognition of one or more B2 haplotype MHC molecules. Finally, TCR downregulation during MDV infection in the MHC-matched model was strongest in the MD-susceptible line, and MDV reactivation downregulated TCR expression in a tumor cell line.